Perampanel (Fycompa)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Partial-onset (focal) seizures with or without secondarily generalized seizures | ≥4 years | Monotherapy or adjunctive | FDA Approved |
| Primary generalized tonic-clonic (PGTC) seizures | ≥12 years | Adjunctive therapy | FDA Approved |
Perampanel was first approved in the United States in 2012 as the first-in-class selective non-competitive AMPA receptor antagonist for epilepsy. Subsequent label expansions have broadened use to include monotherapy for partial-onset seizures (2017), adjunctive therapy for PGTC seizures (2015), and pediatric patients as young as 4 years (2018). In three pivotal Phase 3 trials for partial-onset seizures (Studies 1, 2, and 3; total N=1,480), perampanel 8 mg and 12 mg once daily produced statistically significant reductions in seizure frequency compared with placebo. In a single Phase 3 trial for PGTC seizures (Study 4; N=164), perampanel 8 mg demonstrated a 76.5% median reduction in PGTC seizure frequency versus 38.4% for placebo.
Other generalized epilepsy syndromes (myoclonic, absence) — Limited observational data suggest potential benefit in some generalized epilepsy subtypes beyond PGTC. Evidence quality: Very low.
Post-stroke epilepsy — Small retrospective series suggest reasonable efficacy and tolerability when used at lower doses (4–6 mg). Evidence quality: Very low.
Dosing
Partial-Onset Seizures (Monotherapy or Adjunctive, ≥4 Years)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Focal epilepsy — without concomitant CYP3A4 inducers | 2 mg QHS | 8–12 mg QHS | 12 mg/day | Increase by 2 mg/day no more frequently than weekly; some patients respond at 4 mg 12 mg produces somewhat greater seizure reduction but substantially more adverse effects |
| Focal epilepsy — with concomitant CYP3A4 inducers (CBZ, PHT, OXC) | 4 mg QHS | 8–12 mg QHS | 12 mg/day | CYP3A4 inducers reduce perampanel levels by 50–67%; start at double the standard starting dose Adjust dose when enzyme inducers are added or withdrawn |
Primary Generalized Tonic-Clonic Seizures (Adjunctive, ≥12 Years)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PGTC seizures — without concomitant CYP3A4 inducers | 2 mg QHS | 8 mg QHS | 12 mg/day | Increase by 2 mg/day no more frequently than weekly; may increase to 12 mg if 8 mg tolerated but insufficient 76.5% median seizure reduction at 8 mg vs 38.4% placebo in Phase 3 |
| PGTC seizures — with concomitant CYP3A4 inducers | 4 mg QHS | 8–12 mg QHS | 12 mg/day | Same enzyme-inducer adjustments as for partial-onset seizures Closely monitor when inducers are introduced or withdrawn |
Special Population Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Mild hepatic impairment (Child-Pugh A) | 2 mg QHS | 2–6 mg QHS | 6 mg/day | Titrate by 2 mg no more frequently than every 2 weeks; AUC increased 50% t½ prolonged to ~306 h |
| Moderate hepatic impairment (Child-Pugh B) | 2 mg QHS | 2–4 mg QHS | 4 mg/day | AUC increased 2.55-fold; free perampanel AUC 3.3-fold higher t½ prolonged to ~295 h |
| Severe hepatic impairment (Child-Pugh C) | Not recommended | Not studied; given the marked exposure increases with moderate impairment, use is not recommended | ||
| Elderly (≥65 years) | 2 mg QHS | 4–8 mg QHS | 12 mg/day | Increase no more frequently than every 2 weeks; increased risk of dizziness, falls, and somnolence Clearance similar to younger adults (~10.5 vs 10.9 mL/min) |
Perampanel should always be administered at bedtime because dizziness and somnolence are its most common dose-limiting adverse effects. Its extremely long terminal half-life (~105 hours) means steady state takes approximately 2–3 weeks to achieve, and missed doses have minimal acute impact on seizure control. However, this also means that adverse effects from a dose increase may not fully manifest for 2–3 weeks. The effective half-life (~48 hours) better reflects the clinical duration of action for once-daily dosing. Tablets can be swallowed whole, chewed, or crushed; the oral suspension can be used when tablets are not feasible.
Pharmacology
Mechanism of Action
Perampanel is a first-in-class selective, non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is heavily implicated in seizure generation and propagation. By binding to an allosteric site on the AMPA receptor, perampanel produces a slow, concentration-dependent inhibition of AMPA-mediated currents without affecting NMDA or kainate receptor function. This selective blockade reduces glutamatergic excitatory transmission, dampening neuronal hyperexcitability. The precise mechanism by which this translates into clinical seizure suppression remains incompletely understood, but AMPA receptor antagonism represents a fundamentally different target from sodium channel or GABAergic drugs, offering complementary activity in drug-resistant epilepsy.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid and complete (~100% bioavailability); negligible first-pass metabolism; Tmax 0.5–2.5 h (fasted); food delays Tmax by 1–3 h and reduces Cmax by 28–40% but does not alter AUC | Can be taken with or without food; bedtime dosing recommended to mitigate CNS effects |
| Distribution | Vd ~1.1 L/kg (~77 L); 95–96% plasma protein bound (albumin, α1-acid glycoprotein) | High protein binding means potential for displacement interactions (though not clinically demonstrated); distributes into total body water |
| Metabolism | Extensive hepatic oxidation (>90%) via CYP3A4/5 (primary), CYP1A2 and CYP2B6 (minor); sequential glucuronidation; all metabolites pharmacologically inactive; unchanged drug 74–80% of circulating radioactivity | Highly susceptible to CYP3A4 inducers (CBZ, PHT, OXC reduce levels 50–67%); CYP3A4 inhibitors have modest effects; does not meaningfully inhibit or induce CYP enzymes |
| Elimination | t½ ~105 h (terminal); effective t½ ~48 h; clearance ~12 mL/min; 22% urinary, 48% fecal (primarily as metabolites); with enzyme-inducing AEDs t½ reduced to ~25 h | Supports once-daily dosing; steady state in 2–3 weeks; dose titration no faster than weekly; blood levels decline gradually even after abrupt cessation; not expected to be removed by dialysis |
Side Effects
| Adverse Effect | Incidence (8 mg / 12 mg) | Clinical Note |
|---|---|---|
| Dizziness | 32% / 43% (vs 9% placebo) | Most common adverse effect overall; strongly dose-related; includes vertigo in a subset; led to discontinuation in 3% of treated patients |
| Somnolence | 16% / 18% (vs 7% placebo) | Dose-dependent; occurs mostly during titration; bedtime dosing partially mitigates |
| Fatigue (incl. asthenia, lethargy) | 8% / 12% (vs 5% placebo) | Overlaps with somnolence reporting; combined somnolence + fatigue led to discontinuation in 2% of patients |
| Irritability | 7% / 12% (vs 3% placebo) | Part of the broader hostility/aggression spectrum; dose-related; appears within first 6 weeks |
| Headache | 11% / 13% (vs 11% placebo) | Marginal excess over placebo; generally mild |
| Falls | 5% / 10% (vs 3% placebo) | Can lead to serious injuries including head injuries and fractures; elderly at increased risk |
| Adverse Effect | Incidence (8 mg / 12 mg) | Clinical Note |
|---|---|---|
| Ataxia | 3% / 8% (vs 0% placebo) | Strongly dose-related; gait disturbance events (including balance disorder, abnormal coordination) seen in 12–16% at 8–12 mg vs 2% placebo |
| Nausea | 6% / 8% (vs 5% placebo) | Usually mild and transient; vomiting reported in 3–4% of treated patients |
| Vertigo | 3% / 5% (vs 1% placebo) | Contributes to the dizziness/gait disturbance spectrum |
| Weight gain | 4% / 4% (vs 1% placebo) | Average 1.1 kg (2.5 lbs) vs 0.3 kg (0.7 lbs) placebo over ~19 weeks; 9.1% gained ≥7% body weight vs 4.5% placebo; elevated triglycerides also reported |
| Dysarthria | 3% / 4% (vs 0% placebo) | Slurred speech; dose-related; may be dose-limiting |
| Anxiety | 3% / 4% (vs 1% placebo) | Part of the psychiatric adverse effect profile |
| Blurred vision | 3% / 4% (vs 1% placebo) | Includes diplopia (1–3%); generally reversible with dose reduction |
| Aggression | 2% / 3% (vs 1% placebo) | Part of the boxed warning; hostility/aggression-related events seen in 12–20% at 8–12 mg vs 6% placebo |
| Anger | 1% / 3% (vs <1% placebo) | Part of the serious psychiatric/behavioural reaction profile covered by the boxed warning |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious psychiatric/behavioural reactions (hostility, aggression, homicidal ideation) | 12–20% hostility/aggression at 8–12 mg (vs 6% placebo); homicidal ideation 0.1% | Generally within first 6 weeks; new events through >37 weeks | Reduce dose if symptoms occur; discontinue immediately if severe or worsening; monitor for at least 1 month after last dose; avoid alcohol |
| Suicidal behaviour / ideation | 0.43% (AED class risk) | Within first week; persists during treatment | Implement mood monitoring at every visit; balance risk against untreated epilepsy |
| Falls with serious injury | 5–10% at 8–12 mg (vs 3% placebo); some serious (head injuries, fractures) | Mostly during titration | Assess fall risk, especially in elderly; consider dose reduction; modify environment |
| DRESS / multi-organ hypersensitivity | Rare (postmarketing) | Variable | Discontinue if no alternative aetiology established; evaluate for hepatic, renal, and haematologic involvement |
| Psychosis / delirium (postmarketing) | Rare (postmarketing: acute psychosis, hallucinations, delusions, paranoia) | Variable; more common at higher doses | Discontinue permanently; refer for psychiatric evaluation |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Dizziness | ≥1% (8 mg and 12 mg groups) | Most common reason for stopping; strongly dose-related |
| Somnolence | ≥1% (8 mg and 12 mg groups) | Often combined with fatigue and gait disturbance |
| Aggression / anger / irritability | ≥1% (8 mg and 12 mg groups) | Part of the boxed warning spectrum; more at 12 mg |
| Vertigo / ataxia / blurred vision | ≥1% (primarily 12 mg group) | Neurological effects leading to dose reduction or discontinuation |
Perampanel carries a boxed warning for serious psychiatric and behavioural reactions. Hostility and aggression-related events occurred in up to 20% of patients at 12 mg/day versus 6% on placebo, and homicidal ideation/threats were reported in 0.1% of all exposed patients. These events occurred in patients with and without prior psychiatric history, and alcohol use significantly worsened mood and increased anger. The key management strategies are: use the lowest effective dose (consider 8 mg rather than 12 mg given the steep dose-toxicity curve), avoid concurrent alcohol, monitor mood and behaviour at every visit particularly during the first 6 weeks and at dose increases, and reduce or discontinue the dose promptly if symptoms emerge. Continue monitoring for at least one month after the last dose.
Drug Interactions
Perampanel is predominantly metabolised by CYP3A4/5, making it highly susceptible to CYP3A4 inducers. It does not meaningfully inhibit or induce major CYP enzymes at therapeutic doses. The most clinically significant interactions involve enzyme-inducing antiseizure medications that substantially reduce perampanel exposure, and the pharmacodynamic potentiation of CNS depression with alcohol.
Perampanel does not meaningfully affect plasma levels of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, or zonisamide. CYP3A4 inhibitors (e.g., ketoconazole) have only modest effects on perampanel exposure that do not require dose adjustment. At doses ≤8 mg/day, perampanel does not affect hormonal contraceptive efficacy.
Monitoring
- Mood & BehaviourEvery visit + first 6 weeks closely
RoutineEssential given the boxed warning. Screen for aggression, hostility, irritability, anger, homicidal ideation, depression, and suicidal thoughts. Monitor during titration, at dose increases, and for at least 1 month after the last dose. Educate families and caregivers. - Seizure FrequencyEvery visit
RoutineSeizure diary review. Steady state takes 2–3 weeks; assess efficacy no sooner than 2–3 weeks after each dose change. Consider whether 8 mg provides sufficient control before increasing to 12 mg. - Falls / GaitEvery visit
RoutineFalls reported in 5–10% of patients at therapeutic doses; elderly at increased risk. Assess gait, balance, and fall history. Modify environment and consider dose reduction if recurrent falls. - WeightEvery visit
RoutineWeight gain is common (average 1.1 kg over 19 weeks; 9.1% gained ≥7% body weight). Also consider fasting lipids as increased triglycerides have been reported. - Hepatic FunctionBaseline
RoutineAssess hepatic status to determine dose cap: mild impairment max 6 mg, moderate max 4 mg, severe — not recommended. Half-life prolongs markedly (to ~295–306 h) in hepatic impairment. - DRESS SymptomsOngoing
Trigger-basedEvaluate immediately if fever, rash, lymphadenopathy, or facial swelling develop. DRESS may present without rash initially. Discontinue if no alternative aetiology identified.
Contraindications & Cautions
Absolute Contraindications
- None listed in FDA labeling — The FDA PI states "None" under contraindications. However, hypersensitivity to perampanel or any excipient should preclude use as with any medication.
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child-Pugh C) — Not recommended; AUC more than doubles in moderate impairment with marked half-life prolongation.
- Severe renal impairment or hemodialysis — Not recommended; not studied in this population; highly protein-bound, unlikely to be dialysable.
- Active psychotic disorder or history of serious aggression — Given the boxed warning for hostility, aggression, and homicidal ideation; use requires careful risk–benefit assessment.
- Active suicidal ideation — All AEDs carry a class-wide suicidality risk; perampanel additionally enhances anger and depression when combined with alcohol.
Use with Caution
- Elderly patients (≥65 years) — Increased risk of dizziness, falls, and somnolence; titrate no more frequently than every 2 weeks.
- Patients at risk for falls — Falls with serious injuries (head injuries, fractures) reported at rates of 5–10% at therapeutic doses.
- History of substance abuse — Perampanel is Schedule III; supratherapeutic doses produce euphoria and dissociative effects comparable to ketamine.
- Women using levonorgestrel-containing contraception — 12 mg/day reduces levonorgestrel exposure by ~40%; advise additional non-hormonal contraception.
- Pregnancy — Teratogenic in rats and rabbits at clinically relevant doses; visceral abnormalities observed at all doses tested.
Serious or life-threatening psychiatric and behavioural adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking perampanel. These reactions occurred in patients with and without prior psychiatric history. Hostility- and aggression-related events were reported in 12% and 20% of patients at 8 mg and 12 mg/day respectively, versus 6% with placebo. Homicidal ideation/threats were reported in 0.1% of all treated patients (4,368 across controlled and open-label trials). Monitor closely, particularly during titration and at higher doses. Reduce dose if symptoms occur; discontinue immediately if severe or worsening. Alcohol significantly worsens mood and increases anger in patients taking perampanel.
Pooled analysis of 199 placebo-controlled trials of 11 different AEDs demonstrated approximately double the risk of suicidal thinking or behaviour compared with placebo (adjusted RR 1.8; 95% CI 1.2–2.7). The estimated incidence was 0.43% in AED-treated patients versus 0.24% in those receiving placebo.
Patient Counselling
Purpose of Therapy
Perampanel is a medicine that works by blocking a specific type of receptor in the brain called the AMPA receptor, which is involved in the transmission of excitatory signals between nerve cells. By reducing this excessive signalling, perampanel helps control seizures. It is the first medicine in its class and offers a different mechanism from most other seizure medications.
How to Take
Take perampanel once daily at bedtime. This timing helps reduce the impact of dizziness and drowsiness. Tablets may be swallowed whole, chewed, or crushed and added to food or liquid. The oral suspension should be shaken well and measured using the provided syringe. Do not use a household spoon. Discard unused suspension 90 days after opening. Do not stop perampanel suddenly without medical advice, though its long duration in the body means levels will decline gradually.
Sources
- FYCOMPA (perampanel) tablets and oral suspension [prescribing information]. Coral Gables, FL: Catalyst Pharmaceuticals, Inc.; Revised June 2023. FDA LabelPrimary source for all dosing, PK parameters, adverse reactions, drug interactions, boxed warning, and regulatory warnings cited in this monograph.
- European Medicines Agency. Fycompa (perampanel) Summary of Product Characteristics. Eisai Europe Ltd. EMA EPAREuropean regulatory document providing complementary safety and efficacy data, including EU-specific indications and post-marketing updates.
- French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79(6):589–596. doi:10.1212/WNL.0b013e3182635735Pivotal Phase 3 study (Study 1) evaluating perampanel 8 and 12 mg/day vs placebo in 388 adults with refractory partial-onset seizures.
- French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia. 2013;54(1):117–125. doi:10.1111/j.1528-1167.2012.03638.xPivotal Phase 3 study (Study 2) evaluating perampanel 8 and 12 mg/day vs placebo in 386 patients with refractory POS.
- Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78(18):1408–1415. doi:10.1212/WNL.0b013e318254473aPivotal Phase 3 study (Study 3) evaluating perampanel 2, 4, and 8 mg/day vs placebo in 706 patients; demonstrated dose-response relationship.
- French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology. 2015;85(11):950–957. doi:10.1212/WNL.0000000000001930Phase 3 trial (Study 4) establishing adjunctive efficacy of perampanel 8 mg for primary generalized tonic-clonic seizures (76.5% vs 38.4% median reduction).
- Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy. Neurology. 2018;91(2):82–90. doi:10.1212/WNL.0000000000005756AAN/AES guideline reviewing newer AEDs for treatment-resistant epilepsy; Level B recommendation for adjunctive perampanel in refractory focal seizures.
- Hanada T, Hashizume Y, Tokuhara N, et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia. 2011;52(7):1331–1340. doi:10.1111/j.1528-1167.2011.03109.xKey preclinical study characterising the selective non-competitive AMPA receptor antagonism and anticonvulsant activity of perampanel in multiple seizure models.
- Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand. 2013;127(Suppl 197):19–24. doi:10.1111/ane.12100Comprehensive review of the preclinical pharmacology and selectivity of perampanel for AMPA over NMDA and kainate receptors.
- Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia. 2015;56(1):12–27. doi:10.1111/epi.12865Definitive PK review establishing the 100% bioavailability, 105 h terminal half-life, 48 h effective half-life, and CYP3A4-dependent metabolism profile.
- Villanueva V, Montoya J, Castillo A, et al. Perampanel in routine clinical use in idiopathic generalized epilepsy: the 12-month GENERAL study. Epilepsia. 2018;59(9):1740–1752. doi:10.1111/epi.14536Real-world study of perampanel in generalized epilepsy; provides retention rates and tolerability data in clinical practice settings.
- Steinhoff BJ, Hamer H, Trinka E, et al. A multicenter survey of clinical experiences with perampanel in real life in Germany and Austria. Epilepsy Res. 2014;108(5):986–988. doi:10.1016/j.eplepsyres.2014.03.013Early real-world experience highlighting the clinical significance of psychiatric adverse effects and the importance of slow titration.